Genetic Variant NM_001378373.1:c.303G>T (chr10-52770671-C-A) – ACMG Classification: Likely_benign (-3 pts)

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PM2BP4_StrongBP7

The NM_001378373.1(MBL2):c.303G>T(p.Pro101Pro) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000076 in 1,315,206 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. P101P) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 7.6e-7 ( 0 hom. )

Consequence

MBL2
NM_001378373.1 splice_region, synonymous

Scores

Splicing: ADA: 0.0001385

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.0890

Publications

0 publications found

Variant links:

Genes affected

MBL2 (HGNC:6922): (mannose binding lectin 2) This gene encodes the soluble mannose-binding lectin or mannose-binding protein found in serum. The protein encoded belongs to the collectin family and is an important element in the innate immune system. The protein recognizes and binds to mannose and N-acetylglucosamine on many microorganisms, including bacteria, yeast, and viruses including influenza virus, HIV and SARS-CoV. This binding activates the classical complement pathway. Deficiencies of this gene have been associated with susceptibility to autoimmune and infectious diseases. [provided by RefSeq, Jun 2020]

MBL2 links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.83).

BP7

Synonymous conserved (PhyloP=0.089 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MBL2	NM_001378373.1 link	c.303G>T	p.Pro101Pro	splice_region_variant, synonymous_variant	Exon 3 of 5	ENST00000674931.1	NP_001365302.1
MBL2	NM_000242.3 link	c.303G>T	p.Pro101Pro	splice_region_variant, synonymous_variant	Exon 2 of 4		NP_000233.1	P11226
MBL2	NM_001378374.1 link	c.303G>T	p.Pro101Pro	splice_region_variant, synonymous_variant	Exon 3 of 5		NP_001365303.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
MBL2	ENST00000674931.1 link	c.303G>T	p.Pro101Pro	splice_region_variant, synonymous_variant	Exon 3 of 5		NM_001378373.1	ENSP00000502789.1	P11226
MBL2	ENST00000373968.3 link	c.303G>T	p.Pro101Pro	splice_region_variant, synonymous_variant	Exon 2 of 4	1		ENSP00000363079.3	P11226
MBL2	ENST00000675947.1 link	c.303G>T	p.Pro101Pro	splice_region_variant, synonymous_variant	Exon 3 of 5			ENSP00000502615.1	P11226

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

7.60e-7

AC:

AN:

1315206

Hom.:

Cov.:

AF XY:

0.00000154

AC XY:

AN XY:

649974

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

27884

American (AMR)

AF:

0.00

AC:

AN:

29738

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

20552

East Asian (EAS)

AF:

0.00

AC:

AN:

33828

South Asian (SAS)

AF:

0.0000159

AC:

AN:

62940

European-Finnish (FIN)

AF:

0.00

AC:

AN:

48890

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5118

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1033474

Other (OTH)

AF:

0.00

AC:

AN:

52782

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.275

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.83

CADD

Benign

2.2

(source)

DANN

Benign

0.29

PhyloP100

0.089

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.00014

dbscSNV1_RF

Benign

0.0080

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over